The objective is to study experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), focusing on how the innate and adaptive immune systems interact to trigger and regulate the disease. Two Specific Aims are proposed. AIM 1 tests the hypothesis that the innate immune system contributes to the triggering of EAE. We will use Lewis (LEW) rats tolerized with MBP68-86 + incomplete adjuvant. These rats are protected against EAE, and ex vivo transfer of T cells from tolerant donors confers protection on LEW recipients. These rats also harbor encephalitogenic T cells that transfer EAE after in vitro culture with MBP68-86. Thus, pathogenic and suppressor (Treg) cells coexist in tolerized hosts, which provides a unique model to study triggering events in EAE. It has been reported that microbial CpG oligonucleotides, which interact with Toll-like receptors (TLRs) on APCs and trigger production of IL-12, promote inflammatory Thl responses. In Aim 1 we will test the hypothesis that CpG will activate the encephalitogenic T cells, thus overcoming the regulatory function of Treg cells which normally prevent EAE in these animals. [unreadable] [unreadable] Aim 2 determines the mechanism by which natural killer (NK) cells, which are important components of the innate immune system, suppress T cell activation. It has been reported that NK cell depletion leads to exacerbation of EAE, and we have shown that NK cells inhibit the proliferation of activated encephalitogenic T cells. We will test the hypothesis that NK cells maintain immune homeostasis by preventing the inadvertent activation of autoreactive T cell clones that otherwise could elicit EAE. In Aim 2 we will determine the mechanism by which NK cells suppress T cell activation. [unreadable] [unreadable] These studies will provide new insight into how microbes activate autoreactive T cells, and clarify the roles of innate and adaptive immunity in regulation of EAE by NK and Treg cells, respectively. [unreadable] [unreadable]